Embolization is the selective blockage of one or more blood vessels supplying a diseased vascular structure or diseased tissue while simultaneously preserving the blood supply to surrounding normal vascular structure or tissue. For example, uterine fibroid embolization (UFE) is the process of occluding the vascular blood supply to uterine fibroids to reduce fibroid size and alleviate associated symptoms, including bleeding, pain, and disfigurement. Fibroids are benign tumors of smooth muscle. They are also called leiomyomas or myomas. Fibroids may arise in different parts of the uterus. They are named by their position within the uterus; submucosal, intramural, and subserosal. Some fibroids grow on a stalk and these are called pedunculated. Abnormal bleeding can be caused by submucosal or intramural fibroids. Intramural and subserosal fibroids can cause pelvic pain, back pain, and generalized pressure sensations. Fibroids often fail to respond to medical therapies, causing either myomectomy (surgical removal of the fibroids) or hysterectomy to be an ultimate treatment. In recent years, there has been considerable research aimed at developing less invasive alternatives to surgical treatments of fibroids. One such alternative is uterine fibroid embolization.
PCT/US99/04398 discloses a method for gynecological endovascular embolization with a fluid embolic composition that halicize forms a coherent solid mass. The embolization agent is a composition of biocompatible polymers and a radiopaque material. In some applications where a water soluble radiopaque material is used, the composition does not contain any particles. The particle size is no more than 100 micrometers and preferably less than 10 micrometers.
U.S. Pat. No. 4,999,188 (Solodovnik et al.) discloses a composition for embolization of blood vessels, in which agglomeration of particles is decreased as the composition is introduced. The proposed composition can additionally comprise a medicinal or radiopaque substance or a mixture of these in an amount of about 0.005 to about 8% by weight in relation to the total weight of the initial ingredients. The particles of the embolizing material may include particles of a polymer material moderately swelling in water, particles of glass or metal or a mixture thereof Suitable polymeric particles include acetylcellulose, acetylphtalylcellulose, polyvinylacetate, copolymers of vinylpyrrolidone and methylmethacrylate.
U.S. Pat. No. 5,202,352 (Okada et al.) discloses an intravascular embolizing agent containing an angiogenesis-inhibiting substance and an intravascular embolizing substance. The agent, with the administration of a relatively small dosage amount, enhances the anti-tumor effect of the angiogenesis-inhibiting substances. The addition of small doses of angiogenesis inhibiting substances also enhances the anti-tumor effect of intravascular embolizing agents.
U.S. Pat. No. 5,236,410 (Granov et al.) discloses a method for tumor treatment which involves first catheterization of the vessel that supplies a tumor of interest. A suspension of a magnetically hard ferromagnetic substance in an oil solution of oil-soluble antitumor agent is then injected through the catheter under fluoroscopic control and, at the same time, local magnetic field is applied onto the tumor-bearing area. After 1-3 days, the tumor is subjected to oscillating power field selected from ultrahigh radio frequency electromagnetic field and the field of ultrasonic contraction waves until the temperature of 43.0-43.5C. is reached within the tumor, and this temperature is maintained for 5-45 minutes. In cases of large size tumors it is preferable to reduce the blood flow in the tumor-feeding blood vessel after the administration thereto of the suspension.
U.S. Pat. No. 5,624,685 (Takahashi et al.) discloses a vascular lesion embolizing material comprising a high-polymer gel capable of absorbing water in an amount of 10 mL/g and more. When the high-polymer gel is supplied, either as such or after being bound with a binder or confined in a capsule, to the site of a blood vessel having a lesion to be repaired or its neighborhood, the gel swells upon contact with blood and spreads readily in the blood vessel to close the lumen of the blood vessels with lesion.
Still another approach to the embolization of an abnormal vascular site is the injection into the site of a biocompatible hydrogel, such as poly (2-hydroxyethyl methacrylate) (“pHEMA” or “PHEMA”); or a polyvinyl alcohol foam (“PAF”). See, e.g., Horak et al., “Hydrogels in Endovascular Embolization. II. Clinical Use of Spherical Particles”, Biomaterials, Vol. 7, pp. 467-470 (November, 1986); Rao et al., “Hydrolysed Microspheres from Cross-Linked Polymethyl Methacrylate”, J. Neuroradiol., Vol. 18, pp. 61-69 (1991); Latchaw et al., “Polyvinyl Foam Embolization of Vascular and Neoplastic Lesions of the Head, Neck, and Spine”, Radiology, Vol. 131, pp. 669-679 (June, 1979). These materials are delivered as microparticles in a carrier fluid that is injected into the vascular site, a process that has proven difficult to control. A further development in this arena has been the formulation of hydrogel materials into a preformed implant or plug that is installed in the vascular site by means such as a microcatheter. See, e.g., U.S. Pat. Nos. 5,258,042—Mehta and 5,456,693—Conston et al. These types of plugs or implants are primarily designed for obstructing blood flow through a tubular vessel or the neck of an aneurysm, and they are not easily adapted for precise implantation within a sack-shaped vascular structure, such as an aneurysm, so as to fill substantially the entire volume of the structure.
As underscored by the preceding overview, the vast majority of the agents used today embolize permanently. However, there are numerous clinical situations, e.g., trauma, postpartum hemorrhage, and GI bleeding, in which temporary embolization is desired. The typical aim of temporary embolization is to block blood flow to the punctured site, allowing the blood vessel to heal over. As a temporary embolization agent degrades, the blood vessel recanalizes, reestablishing the old vasculature.
The temporary embolization agent used most frequently today in the clinical setting is gelfoam. This embolic agent comes in the form of sheets. Physicians cut sheet gelfoam into pieces, and inject them into a vessel through a catheter. Gelfoam is degraded by proteases in the blood stream. However, due to differences in enzyme expression from one patient to another, and variation in the size of the pieces of gelfoam used, the in vivo degradation times of this embolization agent span a wide range, i.e., from hours to weeks. Another temporary embolization agent that has been used clinically is starch microspheres. Starch microspheres degrade rapidly, i.e., within minutes to hours, due to the action of α-amylase; unfortunately, this timeframe is too short for most applications.
Autologous materials, e.g., fat, dura mater, muscle and autologous clot, have also been used for temporary embolization. The main advantage of these materials is their low cost and their inherent biocompatibility. The autologous agent used most frequently is autologous clot. There are several disadvantages associated with using this kind of embolic agent. As noted in connection with gelfoam, the degradation of autologous materials relies on enzymatic action. Because enzyme expression varies from person to person, the degradation time cannot be accurately predicted.
The use of hydrolytically degradable materials for embolization promises to provide a means to exercise control over the in vivo lifetime of an embolus. Importantly, enzyme activity would not be a factor in the degradation rate of the embolus. Further, the quantity and pH of the aqueous solution present at the site of embolization can be predicted accurately. Materials comprising hydrolytically degradable polymers have been used to prepare hydrolytically degradable emboli.
There are two archetypal ways to render a polymeric material hydrolytically degradable. The first way is to use hydrophobic linear polymers, such as poly(lactic acid/glycolic acid) (PLGA), polyanhydrides, polyesters, and polyesteramides, that degrade into soluble monomers and oligomers. For example, PLGA microspheres have been utilized for embolization. While the degradation time could be controlled in vitro, the minimum time for degradation is on the order of weeks. Further, the PLGA microspheres are rigid beads, which means that they cannot deform and regain their shape when pushed through a catheter with a smaller orifice than the diameter of the beads. Additionally, microspheres made of PLGA or other hydrophobic linear polymers degrade by surface erosion. Therefore, as the beads degrade, the diameter of the beads decreases, creating a possibility that the beads will simply get carried further into the vasculature.
A second way to render a polymeric material hydrolytically degradable is the use of crosslinked polymers comprising hydrolytically degradable crosslinks. For example, hydrolytically degrading polymers were synthesized in situ using photopolymerization of monomers in the presence of crosslinkers containing a hydrolytically unstable lactic acid moiety (Sawhney et al, Macromolecules, 26 (1993) 581-587). The degradation time of these polymers was a function of the number of lactic acid moieties incorporated into the crosslinker and the final polymer. Unfortunately, the lactic acid-containing crosslinker must be stored under anhydrous conditions due to its ready hydrolysis. Other crosslinkers have been prepared containing hydrolytically labile carbonate (Bruining et al, Biomaterials 21 (2000) 595-604), ester (Argade et al, Polymer Bulletin 31 (1993) 401-407, and phosphazene moieties (Grosse-Sommer et al, Journal of Controlled Release 40 (1996) 261-267). Hydrogels comprising such crosslinked polymers are not stable under the conditions described above, and start to degrade immediately following placement in an aqueous environment at any pH value.
A crosslinked polymeric material may also be rendered hydrolytically degradable by incorporating crosslinks which are stable under basic or acidic conditions, but which degrade at physiological pH. Ruckenstein et al (Macromolecules, 32 (1999) 3979-3983; U.S. Pat. No. 6,323,360) described a crosslinker, derived from ethylene glycol divinyl ether and methacrylic acid, with this degradation profile. The Ruckenstein et al crosslinker contains hemiacetal functions, accounting for its stability at high pH, and instability under acidic conditions. Likewise, Ulbrich et al (Journal of Controlled Release, 24 (1993)181-190; Ulbrich et al, Journal of Controlled Release, 34 (1995) 155-165; U.S. Pat. Nos. 5,130,479; and 5,124,421) have described a crosslinker, N,O-dimethacryloylhydroxylamine, that is stable only at low pH. The degradation of the Ulbrich et al crosslinker is postulated to occur via base-catalyzed Lossen rearrangement of substituted hydroxamic acids. Notably, none of these approaches has been utilized to prepare temporary embolic particles.
Degradable hydrogel beads that are compliant and resilient are expected to serve as effective emboli. Hydrogel beads of this type would be able to pass through an orifice with a diameter smaller than the diameter of the beads, thus enabling highly selective embolization. Moreover, through bulk degradation, their degradation times can be controlled because it will be only a function of the blood pH, and the number and type of crosslinks.